The neurotrophin receptor, TrkB, serves a pivotal role in neuronal survival and differentiation as well as in synaptic structure, function, and plasticity. TrkB signaling has also been implicated in diverse psychiatric and neurological disorders. Notably, TrkB is activated during and is required for limbic epileptogenesis. Understanding the mechanisms by which TrkB is activated will provide insight into its pleiotropic functions in health and disease. Transactivation refers to the process whereby a given receptor and its downstream signaling is activated by a stimulus that does not interact directly with the receptor, a mechanism distinct from activation of TrkB by neurotrophins such as BDNF. We recently discovered that the divalent cation, zinc, can transactivate TrkB in cultured neurons by an activity dependent and neurotrophin independent mechanism. Whether zinc transactivates TrkB in vivo and, if so, it's physiological and pathological consequences are unknown. This application centers on the hypothesized transactivation of TrkB by zinc, both in vivo and in slices ex vivo. Three levels of analysis will be assessed: biochemical and immunohistochemical measures of pTrkB and TrkB in membranes and tissue ex vivo; potentiation of the hippocampal mossy fiber-CA3 pyramid synapse in slices ex vivo; and epileptogenesis in the kindling and pilocarpine models in vivo. We will determine whether vesicular zinc transactivates TrkB in vivo; whether vesicular zinc is required for LTP of the mossy fiber-CA3 pyramid synapse; and whether vesicular zinc is required for limbic epileptogenesis in vivo. Successful completion of the proposed work will clarify the role of zinc in transactivation of TrkB in vivo and thereby shed light on the activation of TrkB by both neurotrophin and non-neurotrophin ligands. Understanding how TrkB is activated is important because of the seminal role of TrkB signaling in the mammalian nervous system in development and adulthood and in both health and disease. PUBLIC HEALTH RELEVANCE: The neurotrophin receptor, TrkB, serves a pivotal role in the function of the mammalian nervous system in both health and disease. Understanding the mechanisms by which TrkB is activated will provide insight into its many functions in health and disease. Here we will test whether a novel and an unexpected mechanism of activating TrkB, occurs in living mice. That is, we ask whether the divalent cation zinc activates TrkB in vivo.